Whole-exome sequencing for the identification of primary immunodeficiency in children with sepsis-a prospective population-based cohort study (swiss pediatric sepsis study)

Abstract

Aims & Objectives: Life-threatening infections may represent the first manifestation of an underlying primary immunodeficiency (PID), but the role of PIDs in pediatric sepsis is largely unknown. We performed whole-exome sequencing (WES) in a national cohort of children with blood culture-proven bacterial sepsis to characterize the contribution of PID in pediatric sepsis. Methods Population-based prospective study including previously healthy children ≥28days and <17years admitted with community-acquired blood culture-proven sepsis caused by S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, N. meningitidis or S. agalactiae between 2011-09-01 and 2015-12-31. Analysis of WES data was restricted to rare variants (minor allele frequency <1% and <0.01% for homozygous/hemizygous and heterozygous variants, respectively) in PID genes for which an association with increased susceptibility to bacterial infection was previously described. Results 176 children presenting with 185 sepsis episodes underwent WES, with a median age of 52 months (IQR 15.4-126.4), and a male/female ratio of 1.8. A total of 42 unique rare PID variants (2 homozygous, 7 hemizygous, and 33 heterozygous) were found in 44/176 (25%) patients. PIDs included all 8 PID categories as defined by the International Union of Immunological Societies. We did not observe a clinically significant correlation between clinical or laboratory characteristics of patients and the likelihood of finding a PID variant. Conclusions Applying WES to a population-based cohort of previously healthy children with bacterial sepsis revealed mutations associated with PID in one out of four sepsis cases. WES represents a promising approach to investigate children with sepsis for underlying PID, which may have severe consequences if undiagnosed.L6238160602018-09-13 <br />